This study will examine promising but as-yet-unproven biochemical, genetic, and lifestyle predictors of coronary heart disease (CHD) and stroke in a prospective cohort of 121,700 US women currently aged 55-80 years. Blood samples were collected from 32,826 participants in 1989-1990, and detailed nutritional, behavioral, and lifestyle variables have been collected for more than 25 years. A major aim is to compare the predictive capability of several biochemical and genetic markers of inflammation and endothelial activation for CHD versus stroke in women: C-reactive protein (CRP), E-selectin, intercellular adhesion molecule-1, endothelin-1, and polymorphisms of the CRP and E-selectin genes. Few studies have directly compared risk factors for both CHD and stroke, although this information is essential from public health and screening standpoints. This proposed work will also continue the investigation of lifestyle determinants of cardiovascular disease, including hormone replacement therapy (dose, formulation, and duration of use) and alcohol consumption (dose and beverage type), in the full cohort and interactions of these exposures with the above biomarkers and with novel genetic markers (prothrombin and alcohol dehydrogenase-3 gene polymorphisms). By 2004, an estimated 834 cases of CHD (nonfatal myocardial infarction and fatal CHD) and 453 cases of ischemic stroke will have been confirmed among women in the blood cohort, and 3,442 cases of CHD and 1,378 cases of ischemic stroke among women in the overall cohort. The Nurses' Health Study has a long, established record of important findings on predictors of cardiovascular disease in women. The large size, prospective design, high follow-up rates, detailed and reliable long-term exposure and outcome information, and the availability of blood specimens on a large subgroup, combined with the relatively low cost, make this cohort a valuable and unique resource for studying biochemical and genetic determinants of cardiovascular risk in women. The results of this work may lead to new strategies for identifying women at high risk of cardiovascular disease as well as new approaches for cardiovascular disease prevention and treatment.